Our long-term goal is to understand how nuclear receptors regulate macrophage gene expression in health and disease. Nuclear receptors are ligand-activated transcription factors that modulate reproduction, development, and general metabolism. Recent studies indicate that expression of nuclear receptor superfamily is dynamically modulated during macrophage activation, indicating that these receptors play a pivotal role in orchestrating macrophage transcriptional responses. Indeed, work from our laboratory and those of others has shown that Peroxisome Proliferator Activated Receptors (PPARs) play a key regulatory role in macrophage cholesterol and fatty acid metabolism, and has provided the mechanistic basis for the cardioprotective functions of PPARs in coronary artery disease. While the inflammatory and pathogenic functions of macrophages are well appreciated, their homeostatic functions in tissue repair and immune tolerance remain poorly understood. Our preliminary data indicate the nuclear receptors PPAR delta and gamma play a key role in orchestrating macrophage transcriptional programs necessary for debris clearance and tissue regeneration. Moreover, genetic deletion of these receptors in macrophages severely compromises these homeostatic responses, leading to autoimmunity or impaired tissue repair. Therefore, studies proposed in the present grant application will take molecular, cellular, and genetic approaches, including tissue-specific knockouts, to further investigate how PPAR gamma and delta orchestrate macrophage gene expression during injury and repair. Data from these studies will greatly enhance the molecular understanding of how macrophage functions are regulated under physiologic and pathophysiologic conditions, and should lead to identification of new therapeutic targets for treating autoimmunity and/or improving tissue regeneration after injury. The specific aims of this proposal are to: 1) Determine the molecular mechanisms by which macrophage-specific PPAR delta and gamma control tolerogenic responses, 2) Investigate the regulatory role of macrophage-specific PPAR delta and gamma in tissue regeneration and repair, and 3) Generate macrophage-specific PPAR delta/gamma double knockout mice to elucidate their non-redundant functions in macrophages.